Essential role for the p110delta phosphoinositide 3-kinase in the allergic response

Khaled Ali; Antonio Bilancio; Matthew Thomas; Wayne Pearce; Alasdair M Gilfillan; Christine Tkaczyk; Nicolas Kuehn; Alexander Gray; June Giddings; Emma Peskett; Roy Fox; Ian Bruce; Christoph Walker; Carol Sawyer; Klaus Okkenhaug; Peter Finan; Bart Vanhaesebroeck

doi:10.1038/nature02991

Essential role for the p110delta phosphoinositide 3-kinase in the allergic response

Nature. 2004 Oct 21;431(7011):1007-11. doi: 10.1038/nature02991.

Authors

Khaled Ali¹, Antonio Bilancio, Matthew Thomas, Wayne Pearce, Alasdair M Gilfillan, Christine Tkaczyk, Nicolas Kuehn, Alexander Gray, June Giddings, Emma Peskett, Roy Fox, Ian Bruce, Christoph Walker, Carol Sawyer, Klaus Okkenhaug, Peter Finan, Bart Vanhaesebroeck

Affiliation

¹ Ludwig Institute for Cancer Research, 91 Riding House Street, London W1W 7BS, UK.

PMID: 15496927
DOI: 10.1038/nature02991

Abstract

Inflammatory substances released by mast cells induce and maintain the allergic response. Mast cell differentiation and activation are regulated, respectively, by stem cell factor (SCF; also known as Kit ligand) and by allergen in complex with allergen-specific immunoglobulin E (IgE). Activated SCF receptors and high-affinity receptors for IgE (FcvarepsilonRI) engage phosphoinositide 3-kinases (PI(3)Ks) to generate intracellular lipid second messenger signals. Here, we report that genetic or pharmacological inactivation of the p110delta isoform of PI(3)K in mast cells leads to defective SCF-mediated in vitro proliferation, adhesion and migration, and to impaired allergen-IgE-induced degranulation and cytokine release. Inactivation of p110delta protects mice against anaphylactic allergic responses. These results identify p110delta as a new target for therapeutic intervention in allergy and mast-cell-related pathologies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anaphylaxis / enzymology
Anaphylaxis / immunology
Animals
Cell Adhesion / drug effects
Cell Count
Cell Degranulation / drug effects
Cell Movement / drug effects
Class I Phosphatidylinositol 3-Kinases
Cytokines / metabolism
Dermis / cytology
Genes, Essential / genetics
Humans
Hypersensitivity / enzymology*
Hypersensitivity / immunology
Interleukin-3 / pharmacology
Isoenzymes / antagonists & inhibitors
Isoenzymes / genetics
Isoenzymes / metabolism
Mast Cells / cytology
Mast Cells / enzymology*
Mast Cells / immunology
Mast Cells / metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism*
Phosphoinositide-3 Kinase Inhibitors
Receptors, IgE / immunology
Second Messenger Systems / physiology
Stem Cell Factor / pharmacology

Substances

Cytokines
Interleukin-3
Isoenzymes
Phosphoinositide-3 Kinase Inhibitors
Receptors, IgE
Stem Cell Factor
Class I Phosphatidylinositol 3-Kinases
Pik3cd protein, mouse